This research project is concerned primarily with the elucidation of the underlying mechanism associated with cholesterol gallstone formation in man. The basic defect appears to be related to an abnormality in cholesterol metabolism which is responsible for the inability of the liver in certain individuals to synthesize adequate amounts of bile acids to compensate for increased fecal loss. This leads to a diminished bile acid pool. We are currently investigating the pathways which lead to the formation of bile acids and cholesterol and also the nature of the cholesterol precursor sources associated with the catabolic degradation of cholesterol. Normal patients and patients with a bile fistula will be administered various labeled compounds and lipoproteins (mevalonic acid, HDL free cholesterol, HDL cholesterol ester, LDL free cholesterol, LDL cholesterol ester) and the data obtained subjected to simulation analysis and modeling to obtain both qualitative and quantitative information on the kinetics of lipoprotein free and cholesterol ester metabolism. Also the interrelationship cholesterol. With this type of information available it may be possible to assertain how bile acid synthesis and biliary cholesterol secretion are regulated by the availability of their precursor sources.